Desymmetric Hydrogenation of meso-Dicarboxylic Acids.

Efficient transformation of platform chemicals into key intermediates has been increasingly important for the pharmaceutical industry. The development of the catalytic reduction of abundant carboxylic acids with molecular hydrogen has been of both practical and theoretical value. We herein report the homogeneous hydrogenation of dicarboxylic acids with the strategy of desymmetrization. Using a rhodium/bisphosphine catalyst, one carboxyl group of meso-diacids was selectively reduced to yield chiral lactones with satisfactory enantioselectivity. This method provides a straightforward approach to produce chiral lactone intermediates for the manufacture of biotin, telaprevir, and other antivirus drugs. Both experimental and computational investigations were carried out, revealing a novel neighboring group coordination mechanism in the catalytic cycle.

Homogeneous Dearomative Hydrogenation with a Co/P4 N2 Catalyst: A Nucleophilic Approach.

Arene hydrogenation is the most straightforward method to prepare carbo- and heterocycles. However, the high resonance energy prevents aromatic substrates from hydrogenation. Herein the homogeneous, nucleophilic hydrogenation of less electron-rich arenes and heteroarenes is reported. The Co(P4 N2 )H species that has been demonstrated to be a strong hydride donor could deliver a hydride ion to the cyano (hetero)arene substrates. Deuterium labeling experiments supported a Michael-type reaction pathway. Theoretical analyses have been conducted to investigate the hydricity of the catalytically active CoH species and the electrophilicity of the arene substrates. An outlook for the synthesis of more challenging substituted benzenes was proposed based on the in silico modification of the CoH species.

A Tetradentate Ligand Enables Iron-Catalyzed Asymmetric Hydrogenation of Ketones in a CO- or Isocyanide-Free Fashion.

We herein reported the design and synthesis of a ferrocene-based tetradentate ligand that is featured with modular synthesis and rigid skeleton. Its iron(II) complex facilitates asymmetric direct hydrogenation of ketones without the participation of extra strong-field ligand such as CO and isocyanide. Hydride donor lithium aluminum hydride (LAH) converted non-reactive Fe(II) species to reactive Fe(II) hydride species. With this catalyst, various chiral alcohols including the intermediate for montelukast could be prepared with satisfactory yields and enantioinduction.

Distinct brain activity alterations of treatment for bipolar disorders with psychotherapy and drug therapy: activation likelihood estimation meta-analysis.

BACKGROUNDS: Many studies suggest that both psychotherapy and drug therapy are effective in the treatment of bipolar disorders (BDs). However, the pathophysiology of both types of intervention has not been established definitively. METHODS: An activation likelihood estimation meta-analysis was performed to identify the distinct brain activity alterations between psychotherapy and drug therapy for the treatment of BDs. Articles were identified by searching databases including PubMed, Embase, Cochrane Library, and Web of Science databases. Eligible studies on BDs were published up until 10 June 2021. RESULTS: 21 studies were included and we conducted a meta-analysis for different therapies and imaging tasks. After receiving psychotherapy, BD patients showed increased activation in the inferior frontal gyrus (IFG) and superior temporal gyrus. While after taking drug therapy, BD patients displayed increased activation in the anterior cingulate cortex, medial frontal gyrus, IFG, and decreased activation in the posterior cingulate cortex. The regions of brain activity changes caused by psychotherapy were mostly focused on the frontal areas, while drug therapy mainly impacted on the limbic areas. Different type of tasks also affected brain regions which were activated. CONCLUSIONS: Our comprehensive meta-analysis indicates that these two treatments might have effect on BD in their own therapeutic modes. Psychotherapy might have a top-down effect, while drug therapy might have a bottom-up effect. This study may contribute to differential diagnosis of BDs and would be helpful to finding more accurate neuroimaging biomarkers for BD treatment.

Chiral Tridentate Ligands in Transition Metal-Catalyzed Asymmetric Hydrogenation.

Asymmetric hydrogenation (AH) of double bonds has been one of the most effective methods for the preparation of chiral molecules and for the synthesis of important chiral building blocks. In the past 60 years, noble metals with bidentate ligands have shown marvelous reactivity and enantioselectivity in asymmetric hydrogenation of a series of prochiral substrates. In recent years, developing chiral tridentate ligands has played an increasingly important role in AH. With modular frameworks and a variety of functionalities on the side arms, chiral tridentate ligand complexes enable both reactivities and stereoselectivities. Although great achievements have been made for noble metal catalysts with chiral tridentate ligands since the 1990s, the design of chiral tridentate ligands for earth abundant metal catalysts has still been in high demand. This review summarizes the development of chiral tridentate ligands for homogeneous asymmetric hydrogenation. The philosophy of ligand design and the reaction mechanisms are highlighted and discussed as well.

Fast Isomerization Before Isomerization-Hydroformylation: Probing the Neglected Period with A Novel Microfluidic Device.

By combining the concept of flash chemistry and radial synthesis, a novel microreactor (Flashstop reactor) was designed to study isomerization process of hydroformylation by a Rh/tetraphosphite catalyst in a time scale of seconds. It was found that in the initial 313 seconds, 60-99 % of 1-octene was isomerized to 2- and 3-octenes before the formation of aldehydes. Within this period, two different types of isomerization reactions were observed. It was proposed that a monohydride complex without CO ligand accounts for the ultrafast isomerization in the initial 30 seconds. The isomerization rate with such monohydride species was calculated much faster than that with the well-known H(CO)Rh(P-P) species. Both experimental and DFT computational studies were carried out to support this assumption. Fast transformations early on in catalytic cycles have been rarely studied due to the lack of proper tools. We believe that the Flashstop reactor is a powerful tool for analysis of kinetics in gas-liquid biphasic reactions within a time scale of seconds to minutes.

Asymmetric hydrogenation catalyzed by first-row transition metal complexes.

This review provides a comprehensive view of the application of first-row transition metals in asymmetric hydrogenation and asymmetric transfer hydrogenation. The catalytic behavior of 3d metals is significantly different from that of 4d and 5d metals. The replacement of noble metals with first-row transition metals has encountered challenges such as different reaction mechanisms and unexpected deactivation of the catalyst. The potential involvement of a single-electron process has been the most notorious feature of first-row metals. This review aims to give readers a picture of how first-row transition metals catalyze hydrogenation reactions and the corresponding enantioinduction models. Although this article is partitioned according to the substrate type, it is mechanism-oriented and is focused on catalytic systems. A certain catalytic system could be applied in the hydrogenation of different types of double bonds. Similarities within first-row metals and differences from their 4d and 5d congeners were emphasized.

Noncovalent Interaction-Assisted Ferrocenyl Phosphine Ligands in Asymmetric Catalysis.

Noncovalent interactions are ubiquitous in nature and are responsible for the precision control in enzyme catalysis via the cooperation of multiple active sites. Inspired by this principle, noncovalent interaction-assisted transition metal catalysis has emerged recently as a powerful tool and has attracted intense interest. However, it is still highly desirable to develop efficient and operationally convenient ligands along this line with new structural motifs. Based on the specific nature of hydrogen bonding and ion pairing interactions, we developed a series of noncovalent interaction-assisted chiral ferrocenyl phosphine ligands, including Zhaophos, Wudaphos, and miscellaneous SPO-Wudaphos. Due to the assistance of noncovalent interactions, this catalytic mode is capable of achieving transition metal catalyzed asymmetric hydrogenation and other transformations with remarkable improvement of reactivity and selectivity. In some specific challenging cases, this probably represents one of the most productive methods. Moreover, these ligands are easily prepared, air stable, and highly tunable, meeting the requirements of industrial application.In this Account, we give a concise review of recent advances in asymmetric catalysis. By means of hydrogen bonding interactions, Rh- and Ir-Zhaophos complexes exhibited excellent activities and enantioselectivities in asymmetric hydrogenation of a wide range of substrates: C═C bonds of substituted conjugate alkenes with neutral hydrogen bond acceptors, including nitro groups, carbonyl groups (ketones, esters, amides, maleinimides, and anhydrides), ethers, and sulfones; C═N bonds of substituted iminium salts with chloride as an anionic hydrogen bond acceptor, including N-H imines and cyclic imines; N-heteroaromatic compounds with HCl as an additive, including unprotected quinolines, isoquinolines, and indoles; carbocation of substituted oxocarbenium ions. By means of ion pairing interactions, Rh-Wudaphos complexes enabled the catalytic asymmetric hydrogenation of α-substituted unsaturated carboxylic acids, carboxy-directed α,α-disubstituted terminal olefins, and sodium α-arylethenylsulfonates. Rh-SPO-Wudaphos utilized both hydrogen bonding and ion pairing interactions in asymmetric hydrogenation of α-substituted unsaturated carboxylic acids and phosphonic acids. In addition, Zhaophos has achieved highly selective intramolecular reductive amination and inter- and intramolecular asymmetric decarboxylative allylation. Investigations into mechanism implied that noncovalent interactions were involved in the catalytic cycle and played a critical role for both high reactivity and selectivity. Notably, a rare ionic hydrogenation pathway has been proposed in some cases. Furthermore, these catalytic systems have been used in the gram-scale synthesis of natural products and pharmaceuticals.

Asymmetric Hydrogenation of Cationic Intermediates for the Synthesis of Chiral N,O-Acetals.

For over half a century, transition-metal-catalyzed homogeneous hydrogenation has been mainly focused on neutral and readily prepared unsaturated substrates. Although the addition of molecular hydrogen to C=C, C=N, and C=O bonds represents a well-studied paradigm, the asymmetric hydrogenation of cationic species remains an underdeveloped area. In this study, we were seeking a breakthrough in asymmetric hydrogenation, with cationic intermediates as targets, and thereby anticipating applying this powerful tool to the construction of challenging chiral molecules. Under acidic conditions, both N- or O-acetylsalicylamides underwent cyclization to generate cationic intermediates, which were subsequently reduced by an iridium or rhodium hydride complex. The resulting N,O-acetals were synthesized with remarkably high enantioselectivity. This catalytic strategy exhibited high efficiency (turnover number of up to 4400) and high chemoselectivity. Mechanistic studies supported the hypothesis that a cationic intermediate was formed in situ and hydrogenated afterwards. A catalytic cycle has been proposed with hydride transfer from the iridium complex to the cationic sp2 carbon atom being the rate-determining step. A steric map of the catalyst has been created to illustrate the chiral environment, and a quantitative structure-selectivity relationship analysis showed how enantiomeric induction was achieved in this chemical transformation.

Iridium-Catalyzed Enantioselective Hydrogenation of Oxocarbenium Ions: A Case of Ionic Hydrogenation.

Ionic hydrogenation has not been extensively explored, but is advantageous for challenging substrates such as unsaturated intermediates. Reported here is an iridium-catalyzed hydrogenation of oxocarbenium ions to afford chiral isochromans with high enantioselectivities. A variety of functionalities are compatible with this catalytic system. In the presence of a catalytic amount of the Brønsted acid HCl, an α-chloroether is generated in situ and subsequentially reduced. Kinetic studies suggest first-order kinetics in the substrate and half-order kinetics in the catalyst. A positive nonlinear effect, together with the half kinetic order, revealed a dimerization of the catalyst. Possible reaction pathways based on the monomeric iridium catalyst were proposed and DFT computational studies revealed an ionic hydrogenation pathway. Chloride abstraction and the cleavage of dihydrogen occur in the same step.

Facile Synthesis of Enantiopure Sugar Alcohols: Asymmetric Hydrogenation and Dynamic Kinetic Resolution Combined.

An unprecedented Ir/f-amphox-catalyzed asymmetric hydrogenation of racemic 2,3-syn-dihydroxy-1,4-diones is presented involving dynamic kinetic resolution, which produces (1R,2R,3R,4R)-tetraols. This protocol constitutes an efficient and straightforward approach to accessing sugar alcohols bearing four contiguous stereocenters. The strategy exhibits various advantages over existing methods, including excellent yields (up to 98 %), exceptional stereoselectivities (up to 99:1 dr, 99.9 % ee), operational simplicity and substrate generality. Moreover, the nature of the reaction was revealed as a stepwise transformation by in situ Fourier-transform infrared spectroscopy and isolation of intermediates.

Nickel-Catalyzed Desymmetric Hydrogenation of Cyclohexadienones: An Efficient Approach to All-Carbon Quaternary Stereocenters.

Nickel-catalyzed desymmetric hydrogenation has been achieved. With the Ni(OTf)2/(S,S)-Ph-BPE system, a series of γ,γ-disubstituted cyclohexadienones were transformed to the corresponding cyclohexenones with a chiral all-carbon quaternary center at the γ position in high yields (92-98%) and excellent enantioselectivities (92%-99% ee). This catalytic system can also tolerate the desymmetric reaction of spirocarbocyclic cyclohexadienones to produce the corresponding cyclohexenones bearing a chiral spiro quaternary carbon with high yields (94%-98%) and ee values (96%-99% ee). Furthermore, this methodology provides an efficient and concise synthetic route to the intermediate of natural products cannabispirenones A and B.

Homogeneous Hydrogenation with a Cobalt/Tetraphosphine Catalyst: A Superior Hydride Donor for Polar Double Bonds and N-Heteroarenes.

The development of catalysts based on earth abundant metals in place of noble metals is becoming a central topic of catalysis. We herein report a cobalt/tetraphosphine complex-catalyzed homogeneous hydrogenation of polar unsaturated compounds using an air- and moisture-stable and scalable precatalyst. By activation with potassium hydroxide, this cobalt system shows both high efficiency (up to 24 000 TON and 12 000 h-1 TOF) and excellent chemoselectivities with various aldehydes, ketones, imines, and even N-heteroarenes. The preference for 1,2-reduction over 1,4-reduction makes this method an efficient way to prepare allylic alcohols and amines. Meanwhile, efficient hydrogenation of the challenging N-heteroarenes is also furnished with excellent functional group tolerance. Mechanistic studies and control experiments demonstrated that a CoIH complex functions as a strong hydride donor in the catalytic cycle. Each cobalt intermediate on the catalytic cycle was characterized, and a plausible outer-sphere mechanism was proposed. Noteworthy, external inorganic base plays multiple roles in this reaction and functions in almost every step of the catalytic cycle.

Surface Orientation and Temperature Effects on the Interaction of Silicon with Water: Molecular Dynamics Simulations Using ReaxFF Reactive Force Field.

In this work, we use ReaxFF molecular dynamics simulations to investigate the interaction between water molecules and silicon surfaces with different orientations under ambient temperatures of 300 and 500 K. We studied the water adsorption and dissociation processes as well as the silicon oxidation process on the Si (100), (110), and (111) surfaces. The simulation results indicate that water can adsorb on the Si surfaces in the forms of molecular adsorption and dissociative adsorption, making the surfaces terminated by H2O, OH, and H species. The molecular adsorption of H2O dominates the (100) and (110) surfaces, whereas the dissociative adsorption dominates the (111) surface. Besides, the adsorbed hydroxyl oxygen can insert into the Si-Si bond of the substrate to make the surface oxidized, forming the Si-O-Si bonds. Our simulation results also indicate that the (100) surface is mostly terminated by H whereas (111) is mostly terminated by OH. The higher temperature causes more H2O to dissociate and also make all these surfaces more oxidized. Our results are consistent with most experiments. This study sheds lights on the wet oxidation process of Si and Si surface structure evolution in microelectromechanical systems as well as the Si chemical mechanical polishing process.

Rhodium-catalyzed asymmetric hydrogenation of unprotected NH imines assisted by a thiourea.

Asymmetric hydrogenation of unprotected NH imines catalyzed by rhodium/bis(phosphine)-thiourea provided chiral amines with up to 97% yield and 95% ee. (1)H NMR studies, coupled with control experiments, implied that catalytic chloride-bound intermediates were involved in the mechanism through a dual hydrogen-bonding interaction. Deuteration experiments proved that the hydrogenation proceeded through a pathway consistent with an imine.

Flash Organometallic Catalysis Uncovered by Continuous Microfluidic Devices.

The flash organometallic catalysis is a new concept that refers to the study of fast and controlled organometallic catalytic reactions by using microfluidic devices. Flash reactions' kinetics (ms-s scale) is often ignored due to the lack of proper research tool in organometallic chemistry. The development of microfluidic systems offers the opportunity to discover under-studied mechanisms and new reactions. In this concept, the basic theory of kinetic measurement in a microreactor is briefly reviewed and then two examples on studying flash organometallic catalytic transformation are introduced. One example is the discovery of a highly active palladium catalytic species for Suzuki Coupling and the other example is the study of a neglected isomerization catalytic cycle with a time scale of seconds before isomerization-hydroformylation by customized microfluidic devices. The last part is summary and prospect of this new area. Customizing a microfluidic device with good engineering design for a target reaction supports flash reactions' kinetic experimentation and could become a general strategy in chemistry lab.

The design strategies for CRISPR-based biosensing: Target recognition, signal conversion, and signal amplification.

Rapid, sensitive and selective biosensing is highly important for analyzing biological targets and dynamic physiological processes in cells and living organisms. As an emerging tool, clustered regularly interspaced short palindromic repeats (CRISPR) system is featured with excellent complementary-dependent cleavage and efficient trans-cleavage ability. These merits enable CRISPR system to improve the specificity, sensitivity, and speed for molecular detection. Herein, the structures and functions of several CRISPR proteins for biosensing are summarized in depth. Moreover, the strategies of target recognition, signal conversion, and signal amplification for CRISPR-based biosensing were highlighted from the perspective of biosensor design principles. The state-of-art applications and recent advances of CRISPR system are then outlined, with emphasis on their fluorescent, electrochemical, colorimetric, and applications in POCT technology. Finally, the current challenges and future prospects of this frontier research area are discussed.

miR-200b-3p antagomir inhibits neuronal apoptosis in oxygen-glucose deprivation (OGD) model through regulating ß-TrCP.

BACKGROUND: Hypoxia-ischemic brain damage (HIBD) is a primary cause of morbidity and disability in survivors of preterm infants. We previously discovered that miR-200b-3p plays an important role in HIBD via targeting Slit2. This study was designed to identify novel targets of miR-200b-3p and investigate the relationship between miR-200b-3p and its downstream effectors. METHODS AND RESULTS: Cultured primary rat hippocampal neurons were used in the model of oxygen-glucose deprivation (OGD) and RT-qPCR was utilized to detect the alterations of miR-200b-3p in these cells following the OGD. Our study found that the expression of miR-200b-3p was up-regulated in neurons post OGD. Bioinformatics analysis identified that ß transducin repeat-containing protein (ß-TrCP) is a target gene of miR-200b-3p, and our luciferase reporter gene assay confirmed that miR-200b-3p can interact with ß-TrCP mRNA. Hypoxia-ischemic brain damage was induced in three-day-old SD rats and inhibition of miR-200b-3p by injection of antagomir into bilateral lateral ventricles enhanced ß-TrCP expression at both the mRNA and protein levels in rats' brains. TUNEL staining and CCK-8 assays found that the survival of hippocampal neurons in the miR-200b-3p antagomir group was improved significantly (p＜0.05), whereas apoptosis of neurons in the miR-200b-3p antagomir group was significantly decreased (p＜0.05), as compared with the OGD group. However, silencing of ß-TrCP by ß-TrCP siRNA impaired the neuroprotective effect of miR-200b-3p antagomir. H&E staining showed that miR-200b-3p attenuated the pathological changes in the hippocampal region of rats with HIBD. CONCLUSION: Our study has demonstrated that ß-TrCP is a target gene of miR-200b-3p and that inhibition of miR-200b-3p by antagomir attenuates hypoxia-ischemic brain damage via ß-TrCP.

Carbon dots-based fluorescence enhanced probe for the determination of glucose.

In this work, a novel "turn-on" fluorescence sensor for the detection of H2O2 and glucose was developed based on green fluorescent carbon dots (CDs). The CDs was newly prepared by a facile one-pot hydrothermal method with Eosin Y and branched polyethylenimine as precursors. Interestingly, in the presence of H2O2 and HRP, the fluorescence of the CDs enhanced significantly with a red-shift emission due to their "aggregation". Meanwhile, the oxidation of glucose catalyzed by glucose oxidase could generate H2O2. Thus, a simple sensing system based on the CDs as fluorescent probes was constructed for H2O2 and glucose determination, avoiding the fluorescence quenching and subsequent recovery process in conventional turn-on strategy. The method showed good selectivity and sensitivity for glucose sensing with the detection limit of 0.12 µM. The method was further applied to glucose detection in real samples. The obtained results demonstrated the simplicity, selectivity and practicality of the method. This work expands the carbon nanomaterials with fluorescence emission enhancement properties. It provides a new and direct "turn-on" strategy for H2O2 and glucose detection, which could be a simple and effective tool for screening biological substances involved in H2O2-generation reaction.